Certain adamantane derivatives have been used to treat illnesses. Rimantadine (1-(1-aminoethyl)adamantane) is used for the prophylaxis and treatment of influenza in humans. Amantadine has been used for the treatment of both influenza and Parkinson""s disease (Schwab et al., J. Am. Med. Assoc. (1969) 208:1168). Another derivative, memantine, is currently under clinical investigation for the treatment of various neurodegenerative diseases and has been licensed for the treatment of Parkinson""s associated spasticity in Germany (Schneider et al., Dtsch. Med. Wschr. (1984) 109:987).
Memantine protects cortical and retinal neuron cultures from the toxicity of glutamate, NMDA and the HIV-1 coat protein gp120 (Dreyer et al., Science (1990) 248:364). Recent studies demonstrate that it prevents quinolinic acid-induced hippocampal damage in rats (Kelhoff and Wolf., Eur. J. Pharmacol. (1992) 219:451). Memantine demonstrates antiphypoxic properties in vitro and in vivo. It is thought that memantine exerts a neuroprotective effect because it is a micromolar antagonist of the NMDA receptor (Bormann J., Eur. J. Pharmacol. (1989) 166:591).
While memantine is being used to treat neurological disorders, the variety and severity of neurological diseases presents a need for other neuroprotective agents. The present invention provides novel compounds, compositions and methods for the treatment of neurological diseases. The present invention also provides methods of making the novel compounds.
The present invention provides compounds that can be used in the treatment of neurological diseases. The compounds are of the following formula or pharmaceutically acceptable salts thereof: 
The groups R1, R2, R3, R4 and R5 of the formula are independently defined. R1 is H, alkyl, heteroalkyl, aryl, heteroaryl, C(O)OR6 or C(O)R6. R2 is H, alkyl, heteroalkyl, aryl, heteroaryl, C(O)OR6 or C(O)R6. R3 is H, alkyl, heteroalkyl, aryl or heteroaryl. R4 is H, alkyl, heteroalkyl, aryl or heteroaryl. R5 is OR7, alkyl-OR7 or heteroalkyl-OR7. R6 is alkyl, heteroalkyl, aryl or heteroaryl. R7 is NO2, C(O)R6, C(O)alkyl-ONO2 or C(O)heteroalkyl-ONO2. The following substituents are preferred: R1 and R2 are H; R3 and R4 are H or alkyl; and, R7 is NO2 or C(O)alkyl-ONO2.
The present invention also provides pharmaceutical compositions that can be used to treat a neurological disorder. The compositions include a pharmaceutically acceptable carrier and one or more compounds of the following formula or pharmaceutically acceptable salts thereof: 
The substituents of the compounds are independently defined. R1 is H, alkyl, heteroalkyl, aryl, heteroaryl, C(O)OR6 or C(O)R6. R2 is H, alkyl, heteroalkyl, aryl, heteroaryl, C(O)OR6 or C(O)R6. R3 is H, alkyl, heteroalkyl, aryl or heteroaryl. R4 is H, alkyl, heteroalkyl, aryl or heteroaryl. R5 is OR7, alkyl-OR7 or heteroalkyl-OR7. R6 is alkyl, heteroalkyl, aryl or heteroaryl. R7 is NO2, C(O)R6, C(O)alkyl-ONO2 or C(O)heteroalkyl-ONO2. The following substituents are preferred: R1 and R2 are H; R3 and R4 are H or alkyl; and, R7 is NO2, or C(O)alkyl-ONO2.
The present invention also provides methods of treating a neurological disorder. The methods include administering to a patient a pharmaceutically acceptable carrier and one or more compounds of the following formula, or pharmaceutically acceptable salts thereof: 
The substituents of the compounds are independently defined. R1 is H, alkyl, heteroalkyl, aryl, heteroaryl, C(O)OR6 or C(O)R6. R2 is H, alkyl, heteroalkyl, aryl, heteroaryl, C(O)OR6 or C(O)R6. R3 is H, alkyl, heteroalkyl, aryl or heteroaryl. R4 is H, alkyl, heteroalkyl, aryl or heteroaryl. R5 is OR7, alkyl-OR7 or heteroalkyl-OR7. R6 is alkyl, heteroalkyl, aryl or heteroaryl. R7 is NO2, C(O)R6, C(O)alkyl-ONO2 or C(O)heteroalkyl-ONO2. The following substituents are preferred: R1 and R2 are H; R3 and R4 are H or alkyl; and, R7 is NO2 or C(O)alkyl-ONO2.
The present invention further provides methods of making compounds of the following formula or pharmaceutically acceptable salts thereof: 
The substituents of the compounds are independently defined. R1 is H, alkyl, heteroalkyl, aryl, heteroaryl, C(O)OR6 or C(O)R6. R2 is H, alkyl, heteroalkyl, aryl, heteroaryl, C(O)OR6 or C(O)R6. R3 is H, alkyl, heteroalkyl, aryl or heteroaryl. R4 is H, alkyl, heteroalkyl, aryl or heteroaryl. R5 is OR7, alkyl-OR7 or heteroalkyl-OR7. R6 is alkyl, heteroalkyl, aryl or heteroaryl. R7 is NO2, C(O)R6, C(O)alkyl-ONO2 or C(O)heteroalkyl-ONO2. The following substituents are preferred: R1 and R2 are H; R3 and R4 are H or alkyl; and, R7 is NO2 or C(O)alkyl-ONO2.
Preferably, the methods involve oxidizing a compound of the following formula: 
Preferably, the methods further involve nitrating a compound of the formula: 
Preferably, the compound is treated with H2SO4 and water in the oxidation step. The nitration step preferably includes treatment with HNO3 and Ac2O.